Toll-Like Receptor 4 Signaling Leads to Severe Fungal Infection Associated with Enhanced Proinflammatory Immunity and Impaired Expansion of Regulatory T Cells

Toll-like receptors (TLRs) present in innate immune cells recognize pathogen molecular patterns and influence immunity to control the host-parasite interaction. The objective of this study was to characterize the involvement of TLR4 in the innate and adaptive immunity to Paracoccidioides brasiliensis, the most important primary fungal pathogen of Latin America. We compared the responses of C3H/HeJ mice, which are naturally defective in TLR4 signaling, with those of C3H/HePas mice, which express functional receptors, after in vitro and in vivo infection with P. brasiliensis. Unexpectedly, we verified that TLR4-defective macrophages infected in vitro with P. brasiliensis presented decreased fungal loads associated with impaired synthesis of nitric oxide, interleukin-12 (IL-12), and macrophage chemotactic protein 1 (MCP-1). After intratracheal infection with 1 million yeasts, TLR4-defective mice developed reduced fungal burdens and decreased levels of pulmonary nitric oxide, proinflammatory cytokines, and antibodies. TLR4-competent mice produced elevated levels of IL-12 and tumor necrosis factor alpha (TNF-alpha), besides cytokines of the Th17 pattern, indicating a proinflammatory role for TLR4 signaling. The more severe infection of TLR4-normal mice resulted in increased influx of activated macrophages and T cells to the lungs and progressive control of fungal burdens but impaired expansion of regulatory T cells (Treg cells). In contrast, TLR4-defective mice were not able to clear their diminished fungal burdens totally, a defect associated with deficient activation of T-cell immunity and enhanced development of Treg cells. These divergent patterns of immunity, however, resulted in equivalent mortality rates, indicating that control of elevated fungal growth mediated by vigorous inflammatory reactions is as deleterious to the hosts as low fungal loads inefficiently controlled by limited inflammatory reactions.

Expansion of CD4(+) CD25(+) Foxp3(+) T cells by bone marrow-derived dendritic cells

Dendritic cells (DCs) are the most important antigen-presenting cells of the immune system and have a crucial role in T-lymphocyte activation and adaptive immunity initiation. However, DCs have also been implicated in maintaining immunological tolerance. In this study, we evaluated changes in the CD4(+) CD25(+) Foxp3(+) T-cell population after co-culture of lymph node cells from BALB/c mice with syngeneic bone marrow-derived DCs. Our results showed an increase in CD4(+) CD25(+) Foxp3(+) T cells after co-culture which occurred regardless of the activation state of DCs and the presence of allogeneic apoptotic cells; however, it was greater when DCs were immature and were pulsed with the alloantigen. Interestingly, syngeneic apoptotic thymocytes were not as efficient as allogeneic apoptotic cells in expanding the CD4(+) CD25(+) Foxp3(+) T-cell population. In all experimental settings, DCs produced high amounts of transforming growth factor (TGF)-beta. The presence of allogeneic apoptotic cells induced interleukin (IL)-2 production in immature and mature DC cultures. This cytokine was also detected in the supernatants under all experimental conditions and enhanced when immature DCs were pulsed with the alloantigen. CD4(+) CD25(+) Foxp3(+) T-cell expansion during co-culture of lymph node cells with DCs strongly suggested that the presence of alloantigen enhanced the number of regulatory T cells (Tregs) in vitro. Our data also suggest a role for both TGF-beta and IL-2 in the augmentation of the CD4(+) CD25(+) Foxp3(+) population.

Center of mass energy and system-size dependence of photon production at forward rapidity at RHIC

We present the multiplicity and pseudorapidity distributions of photons produced in Au + Au and Cu + Cu collisions at root(s)NN = 62.4 and 200 GeV. The photons are measured in the region -3.7 < eta < -2.3 using the photon Multiplicity detector in the STAR experiment at RHIC. The number of photons produced per average number of participating nucleon pairs increases with the beam energy and is independent of (lie collision centrality. For collisions with similar average numbers of participating nucleons the photon multiplicities are observed to be similar for An + Au and Cu + Cu collisions at a given beam energy. The ratios of the number of charged particles to photons in the measured pseudorapidity range are found to be 1.4 +/- 0.1 and 1.2 +/- 0.1 for root(s)NN = 62.4 and 200 GeV, respectively. The energy dependence of this ratio could reflect varying contributions from baryons to charged particles, while mesons are the dominant contributors to photon production in the given kinematic region. The photon pseudorapidity distributions normalized by average number of participating nucleon pairs, when plotted as a function of eta-Y(beam), are found to follow a longitudinal scaling independent of centrality and colliding ion species at both beam energies. (C) 2009 Elsevier B.V. All rights reserved.

Iodine(III)-promoted ring expansion of 1-vinylcycloalkanol derivatives: A metal-free approach toward seven-membered rings

A versatile and metal-free approach for the synthesis of molecules bearing seven- and eight-membered rings is described. The strategy is based on the ring expansion of 1-vinylcycloalkanols (or the corresponding silyl or methyl ether) mediated by the hypervalent iodine reagent HTIB (Phl(OH)OTs). The reaction condition can be easily adjusted to give seven-membered rings bearing different functional groups. A route to medium-ring lactones was also developed.